Stable pharmaceutical composition for oral administration

ABSTRACT

Provided is a stable pharmaceutical composition for oral administration comprising 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide (hereinafter referred to as compound A) or a pharmaceutically acceptable salt thereof, wherein the generation of related substances during storage is inhibited. In the stable pharmaceutical composition for oral administration, the proportion of crystals of compound A or a pharmaceutically acceptable salt thereof is 60% or more with respect to the total amount of compound A or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. patentapplication Ser. No. 18/085,842, filed Dec. 21, 2022, which is acontinuation application of U.S. patent application Ser. No. 17/000,763,filed Aug. 24, 2020, now abandoned, which is a continuation applicationof U.S. patent application Ser. No. 15/741,377, which was the NationalStage of International Application No. PCT/JP2016/069615, filed Jul. 1,2016, now U.S. Pat. No. 10,786,500, and which are all incorporatedherein by reference in their entirety and which claim the benefit ofJapanese Patent Application No. 2015-134817, filed Jul. 3, 2015.

TECHNICAL FIELD

The present invention relates to a stable pharmaceutical composition fororal administration comprising6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamideor a pharmaceutically acceptable salt thereof.

BACKGROUND ART

6-Ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide(hereinafter referred to as compound A in some cases) is a compoundrepresented by the following chemical structural formula. It has beenreported that Compound A or a pharmaceutically acceptable salt thereofhas, for example, an inhibitory activity of a kinase activity of an EML4(Echinoderm microtubule associated protein like-4)-ALK (Anaplasticlymphoma kinase) fusion protein, and is useful as an active ingredientof a pharmaceutical composition for treating cancer (Patent literature1).

From the viewpoint of the safety of the patients, it is desirable thatthe generation of related substances is inhibited during storage of aformulation. For example, the Ministry of Health, Labor and Welfare inJapan published a specification of drug products, namely, the concept ofrelated substances (impurities) in drug products as observed duringstability tests (Pharmaceutical and Food Safety Bureau, Evaluation andLicensing Division Notification No. 0624001 “Revision of the Guidelineon the Impurities in the Medicinal Products with New ActiveIngredients”). According to the revised guideline, for example, when theamount of the drug substance to be administered per day is 10 mg to 100mg, the threshold of related substances requiring safety qualificationin a drug product is the lower of either 0.5% as the percentage of therelated substances contained in the drug substance or 200 μg as thetotal daily intake of the related substances. Therefore, it is useful toprovide a stable formulation comprising Compound A or a pharmaceuticallyacceptable salt thereof, in which the generation of related substancesduring storage is inhibited.

CITATION LIST Patent Literature

[Patent literature 1] WO 2010/128659

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a stable pharmaceuticalcomposition for oral administration comprising Compound A or apharmaceutically acceptable salt thereof, wherein the generation ofrelated substances during storage is inhibited.

Solution to Problem

Compound A hemifumarate is stable in heat and humidity alone, and anincrease in related substances was not observed under certain storageconditions, such as a severity test, or the like, of medicinal products.However, when the pharmaceutical composition of Comparative Example 1described below was prepared, in accordance with an embodiment of a wetgranulation method, a high shear granulation method, by granulatingCompound A hemifumarate together with microcrystalline cellulose and thelike, which did not cause a incompatibility with Compound Ahemifumarate, using water, and drying the granulated product to make aformulation, it was found that related substances unexpectedlyincreased. In order to inhibit the generation of related substances ofCompound A during storage, the inventors conducted intensive studies,and as a result, found that the generation of related substances ofCompound A could be inhibited by inhibiting a decrease in the proportionof crystals of Compound A hemifumarate during the formulation step, andcompleted the present invention.

The present invention provides:

-   [1] a stable pharmaceutical composition for oral administration    comprising    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof, wherein the    proportion of crystals of    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof is 60% or more with    respect to the total amount of    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof;-   [2] the pharmaceutical composition for oral administration of [1],    wherein the percentage of a related substance of    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    is 0.20% or less, after storage of the pharmaceutical composition    for oral administration under opened conditions of 40° C. and 75%    relative humidity for 1 month;-   [3] the pharmaceutical composition for oral administration of [1] or    [2], further comprising a pharmaceutical additive capable of    controlling a water content in a formulation;-   [4] the pharmaceutical composition for oral administration of [3],    wherein the pharmaceutical additive capable of controlling a water    content in a formulation is sugars and/or sugar alcohols;-   [5] the pharmaceutical composition for oral administration of [4],    wherein the sugars and/or sugar alcohols are lactose and/or    D-mannitol;-   [6] the pharmaceutical composition for oral administration of any    one of [3] to [5], wherein the content of the pharmaceutical    additive capable of controlling a water content in a formulation is    20% by weight to 90% by weight with respect to the total weight of    the pharmaceutical composition for oral administration;-   [7] a method of manufacturing a stable pharmaceutical composition    for oral administration, said method comprising:    -   (1) mixing        6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide        or a pharmaceutically acceptable salt thereof with a        pharmaceutical additive capable of controlling a water content        in a formulation,    -   (2) granulating the mixture so that the proportion of crystals        of        6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide        or a pharmaceutically acceptable salt thereof is 60% or more        with respect to the total amount of        6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide        or a pharmaceutically acceptable salt thereof, and    -   (3) compression-molding the granulated product;-   [8] the method of manufacturing a pharmaceutical composition for    oral administration of [7], wherein the granulation is carried out    at a water content of the granulated product of 30% or less;-   [9] the method of manufacturing a pharmaceutical composition for    oral administration [7] or [8], wherein the pharmaceutical additive    capable of controlling a water content in a formulation is sugars    and/or sugar alcohols;-   [10] a method of stabilizing    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof, in a stable    pharmaceutical composition for oral administration comprising    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof, by setting the    proportion of crystals of    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof with respect to the    total amount of    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof to 60% or more, and/or    by adding a pharmaceutical additive capable of controlling a water    content in a formulation;-   [11] use of a pharmaceutical additive capable of controlling a water    content in a formulation in the manufacture of a stable    pharmaceutical composition for oral administration comprising    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof;-   [12] a stable pharmaceutical composition for oral administration    comprising    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof, and lactose and/or    D-mannitol; and-   [13] a stable pharmaceutical composition for oral administration    comprising    6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide    or a pharmaceutically acceptable salt thereof, and D-mannitol.

Advantageous Effects of Invention

According to the present invention, a stable pharmaceutical compositionfor oral administration comprising Compound A or a pharmaceuticallyacceptable salt thereof, wherein the generation of related substancesduring storage is inhibited, can be provided.

DESCRIPTION OF EMBODIMENTS

The term “stable” as used herein means to have stability against, forexample, heat, light, temperature, and/or humidity. For example, after apharmaceutical composition for oral administration is allowed to standunder the following conditions, it is defined as an embodiment in whichrelated substances of Compound A contained in the pharmaceuticalcomposition for oral administration is a specific percentage or less.For example, after a pharmaceutical composition for oral administrationis allowed to stand at 70° C. for 9 days, at 40° C. and 75% relativehumidity (hereinafter X% relative humidity is sometimes abbreviated asX% RH) for 6 months in an embodiment, at 40° C. and 75% RH for 3 monthsin an embodiment, at 40° C. and 75% RH for 1 month in an embodiment, at25° C. and 60% RH for 12 months in an embodiment, at 25° C. and 60% RHfor 6 months in an embodiment, at 25° C. and 60% RH for 3 months in anembodiment, and at 25° C. and 60% RH for 1 month in an embodiment, it isdefined as the percentage of related substances of Compound A containedin the pharmaceutical composition for oral administration measured by ahigh-performance liquid chromatographic method (hereinafter sometimesabbreviated as an HPLC method) being, for example, 0.50% or less, 0.20%or less in an embodiment, and 0.10% or less in an embodiment. In anembodiment, after a pharmaceutical composition for oral administrationis allowed to stand under opened conditions of 40° C. and 75% RH for 1month, 3 months, or 6 months, it is defined as the percentage of relatedsubstances of Compound A contained in the pharmaceutical composition fororal administration measured by an HPLC method being, for example, 0.20%or less, and 0.10% or less in an embodiment.

The term “related substance of Compound A” is defined as, for example,an oxidative decomposition product of Compound A, and in an embodiment,a substance having a relative retention time of about 1.06 with respectto the peak of Compound A, as measured by the HPLC method describedbelow. In connection with this, the related substance having a relativeretention time of about 1.06 with respect to the peak of Compound A ispresumed to be an oxidative decomposition product of Compound A.Numerical values used are interpreted as larger variable values, ingeneral, within an experimental error (for example, within the 95%confidence interval for the mean), or within ±10% of the indicatedvalue, and all the values of the variable.

The “proportion of crystals” of Compound A or a pharmaceuticallyacceptable salt thereof is defined as the proportion of crystals withrespect to the total amount of Compound A or a pharmaceuticallyacceptable salt thereof, and can be calculated by near-infraredspectroscopy (NIR), as described below, or the like.

The term “loss on drying” as used herein means the amount of moisturethat is contained in a sample and lost by drying. The loss on drying canbe calculated, for example, by the following equation:

Loss on drying (%)=(weight (mass) reduced by drying/weight (mass) of asample at the beginning of the measurement of loss on drying)×100

More particularly, the loss on drying can be calculated by the followingequation:

Loss on drying (%)=[(weight (mass) of a sample at the beginning of themeasurement of loss on drying−weight (mass) of a sample at the end ofthe measurement of loss on drying)/(weight (mass) of a sample at thebeginning of the measurement of loss on drying)]×100

Compound A or a pharmaceutically acceptable salt thereof, which is usedin the present invention, is easily available, for example, by a methoddescribed in Patent literature 1, or in a similar fashion to that.

Compound A may be in a free form, which does not form a salt, and mayform a pharmaceutically acceptable salt with an acid. Examples of such asalt include an acid addition salt with an inorganic acid, such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid, or the like; and an acid addition saltwith an organic acid, such as formic acid, acetic acid, propionic acid,oxalic acid, malonic acid, succinic acid, fumaric acid, hemifumaricacid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid,carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid,glutamic acid, or the like. These salts can be prepared by conventionalmethods. Hemifumarate may be exemplified in an embodiment.

Compound A or a pharmaceutically acceptable salt thereof exhibits, forexample, an inhibitory activity of a kinase activity of an EML4-ALKfusion protein, and is useful as an active ingredient of apharmaceutical composition for the treatment of cancer.

The dose of compound A or a pharmaceutically acceptable salt thereof canbe appropriately determined depending on individual cases taken intoconsideration, for example, symptoms, age of the patient, sex, or thelike.

For ordinary oral administration, the daily dosage for an adult issuitably 0.001 mg/kg or more to 100 mg/kg or less, preferably 0.005mg/kg to 30 mg/kg, and more preferably 0.01 mg/kg to 10 mg/kg. This isadministered in one dose, or divided into two to four doses per day.

The content of Compound A or a pharmaceutically acceptable salt thereofis, for example, with respect to the weight of a pharmaceuticalcomposition for oral administration, 1% by weight or more to 70% byweight or less, 5% by weight or more to 50% by weight or less in anembodiment, and 10% by weight or more to 40% by weight or less in anembodiment. The amount contained of Compound A or a pharmaceuticallyacceptable salt thereof is, in the whole formulation, 1 mg or more to200 mg or less, 5 mg or more to 150 mg or less in an embodiment, and 40mg or more to 50 mg or less in an embodiment.

The proportion of crystals of Compound A or a pharmaceuticallyacceptable salt thereof, which are used in the present invention, is notparticularly limited, so long as it is within a range where Compound Aor a pharmaceutically acceptable salt thereof is stable during storage.The proportion of the crystals can be calculated by, for example, adifferential scanning calorimeter analysis (DSC analysis) method, apowder X-ray diffraction method, a solid-state NMR method, anear-infrared spectroscopy (NIR) method, or the like.

As a method of calculating the proportion of crystals of Compound Ahemifumarate in Compound A hemifumarate, for example, the spectrum ismeasured, as a near-infrared spectroscopy measurement, by a Fouriertransform near-infrared spectrometer (MPA, Bruker Optics K.K.)(measurement range; 12500 cm⁻¹ to 5800 cm⁻¹, resolution; 8 cm⁻¹, numberof scans; 32), and the obtained spectrum is secondary-differentiated(Savitzky-Golay convolution method), and can be analyzed using anear-infrared spectrum analysis software (for example, OPUS, BrukerOptics K.K.). The pharmaceutical composition for oral administration ispowdered using a mortar and pestle to measure the spectrum. Before thespectrum measurement of the pharmaceutical composition for oraladministration, spectra of preparations, in which crystals of Compound Ahemifumarate are mixed in various proportions, are regression-analyzedby a partial least square method to create a calibration curve, and eachspectrum obtained from the pharmaceutical composition for oraladministration is interpolated into the calibration curve to calculatethe proportion of crystals of Compound A hemifumarate.

The proportion of the crystals is, for example, with respect to thetotal amount of Compound A or a pharmaceutically acceptable saltthereof, 60% or more, 60% or more to 100% or less in an embodiment, 70%or more to 100% or less in an embodiment, 80% or more to 100% or less inan embodiment, 90% or more to 100% or less in an embodiment, 60% or moreto less than 100% in an embodiment, 70% or more to less than 100% in anembodiment, 80% or more to less than 100% in an embodiment, and 90% ormore to less than 100% in an embodiment. In connection with this,numerical values used are interpreted as a larger variable value, ingeneral, within an experimental error (for example, within the 95%confidence interval for the mean), or within ±10% of the indicatedvalue, and all the values of the variable.

The pharmaceutical composition for oral administration of the presentinvention can further comprise a pharmaceutical additive capable ofcontrolling a water content during a formulation step and/or storage(hereinafter sometimes referred to as a pharmaceutical additive capableof controlling a water content in a formulation). The pharmaceuticaladditive capable of controlling a water content in a formulation is notparticularly limited, so long as the additive per se exhibits loss ondrying capable of keeping the composition comprising Compound A or apharmaceutically acceptable salt thereof stable; or a stablepharmaceutical composition for oral administration comprising Compound Aor a pharmaceutically acceptable salt thereof can be provided by keepingthe water content of the composition comprising Compound A or apharmaceutically acceptable salt thereof during a formulation step (inparticular, a granulation step) low, or by further reducing the watercontent in the formulation and maintaining the water content. Examplesof the additive include sugars and/or sugar alcohols, and the additiveis D-mannitol, maltose, maltitol, erythritol, xylitol, lactose (lactosehydrate), sucrose, glucose, sorbitol, trehalose, lactitol, fructose,arabinose, or trehalose in an embodiment, lactose (lactose hydrate) orD-mannitol in an embodiment, and D-mannitol in an embodiment.

The loss on drying of the pharmaceutical additive capable of controllinga water content in a formulation can be measured, for example, in asimilar manner to the Loss on Drying Test, as defined in the GeneralTests of The Japanese Pharmacopoeia, Sixteenth Edition. In anembodiment, the loss on drying can be measured by allowing thepharmaceutical additive to stand under predetermined temperature andhumidity conditions to moisturize it until the weight (mass) reaches aconstant weight (mass), and then by drying it under predeterminedtemperature and humidity conditions until the weight (mass) reaches aconstant weight (mass). In an embodiment, the loss on drying of apharmaceutical additive, as measured by putting the pharmaceuticaladditive into a bottle, allowing the bottle to stand under openedconditions of 40° C. and 75% RH for 1 week, and measuring the loss ondrying after storage by the loss on drying test (for example, HR73Halogen Moisture Analyzer (manufactured by METTLER TOLEDO) is used as anapparatus, and the measurement is carried out until the weight of thesample reaches a constant weight at 80° C.) is, for example, 20% orless, 1.0% or less in an embodiment, 0.5% or less in an embodiment, and0.4% or less in an embodiment.

The loss on drying of a pharmaceutical composition (for example, atablet) can be measured, for example, in a similar manner to the Loss onDrying Test, as defined in the General Tests of The JapanesePharmacopoeia, Sixteenth Edition. In an embodiment, the loss on dryingcan be measured by allowing the pharmaceutical composition (for example,a tablet) to stand under predetermined temperature and humidityconditions to moisturize it until the weight (mass) reaches a constantweight (mass), and then by drying it under predetermined temperature andhumidity conditions until the weight (mass) reaches a constant weight(mass). In an embodiment, the loss on drying of a pharmaceuticalcomposition (for example, a tablet), as measured by putting thepharmaceutical composition (for example, a tablet) into a bottle,allowing the bottle to stand under opened conditions of 40° C. and 75%RH for 1 week, and measuring the loss on drying after storage by theloss on drying test (for example, HR73 Halogen Moisture Analyzer(manufactured by METTLER TOLEDO) is used as an apparatus, and themeasurement is carried out until the weight of the sample reaches aconstant weight at 80° C.) is, for example, 4.0% or less, 3.0% or lessin an embodiment, and 2.0% or less in an embodiment.

The pharmaceutical additive capable of controlling a water content in aformulation may be appropriately added alone, or as a combination of twoor more, in appropriate amounts.

The content is, with respect to the total weight of the pharmaceuticalcomposition for oral administration, for example, 20% by weight or moreto 90% by weight or less, 30% by weight or more to 80% by weight or lessin an embodiment, 40% by weight or more to 70% by weight or less in anembodiment, 50% by weight or more to 70% by weight or less in anembodiment, and 50% by weight or more to 60% by weight or less in anembodiment.

The pharmaceutical composition for oral administration of the presentinvention may be various formulations, such as tablets, capsules,powders, granules, fine granules, dry syrups, or the like. It is atablet or a capsule in an embodiment, and a tablet in an embodiment.

In the pharmaceutical composition for oral administration of the presentinvention, various pharmaceutical additives, such as binders,disintegrating agents, corrigents, effervescent agents, sweeteners,flavors, lubricants, buffers, antioxidants, stabilizers, surfactants,film coating agents, and the like, may be appropriately used, ifdesired, to the extent that the effects of the present invention can beachieved.

Examples of the binders include gum arabic, hypromellose, hydroxypropylcellulose, hydroxyethyl cellulose, and the like

Examples of the disintegrating agents include corn starch, potatostarch, carmellose calcium, carmellose sodium, low substitutedhydroxypropyl cellulose, and the like.

Examples of the corrigents include citric acid, tartaric acid, malicacid, and the like.

Examples of the effervescent agents include sodium bicarbonate, and thelike.

Examples of the sweeteners include saccharin sodium, glycyrrhizic acid,aspartame, stevia, thaumatin, and the like.

Examples of the flavors include lemon, lemon-lime, orange, menthol, andthe like.

Examples of the lubricants include magnesium stearate, calcium stearate,and the like.

Examples of the buffers include citric acid, succinic acid, fumaricacid, tartaric acid, ascorbic acid, and salts thereof; glutamic acid,glutamine, glycine, aspartic acid, alanine, arginine, and salts thereof;magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boricacid, and salts thereof; and the like.

Examples of the antioxidants include citric acid, sodium nitrite,ascorbic acid, L-ascorbic acid stearate ester, sodium hydrogen nitrite,sodium sulfite, α-thioglycerin, sodium edetate, erythorbic acid,cysteine hydrochloride, dried sodium sulfite, potassiumdichloroisocyanurate, soybean lecithin, sodium thioglycolate, sodiumthiomalate, natural vitamin E, tocopherol, d-δ-tocopherol, tocopherolacetate ester, mixed tocopherols concentrate, ascorbic acid palmitate,sodium pyrosulfite, butylhydroxyanisole, 1,3-butylene glycol,benzotriazole,pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate],2-mercaptobenzimidazole, propyl gallate, dibutylhydroxytoluene, and thelike.

The antioxidants also function as stabilizers. Examples of thestabilizers include citric acid; and citric acid hydrate, calciumcitrate, sodium citrate hydrate, sodium dihydrogen citrate, disodiumcitrate, and the like in an embodiment.

Examples of the surfactants include poly sorbate 80, sodium laurylsulfate, polyoxyethylene hydrogenated castor oil, and the like.

Examples of the film coating agents include hypromellose, polyvinylalcohol, and the like.

These pharmaceutical additives may be appropriately added alone, or as acombination of two or more, in appropriate amounts. With respect to thecontents of the pharmaceutical additives, each pharmaceutical additivemay be used in an amount such that the desired effects of the presentinvention may be achieved.

The pharmaceutical composition for oral administration of the presentinvention can be produced by known methods comprising the steps of, forexample, pulverization, mixing, granulation, drying, molding(tableting), film coating, crystallization, and the like. The method ofmanufacturing a pharmaceutical composition for oral administration ofthe present invention will be explained below.

Pulverization Step and Mixing Step

In the pulverization step, both the apparatus and the means are notparticularly limited, so long as it is a method in which Compound A or apharmaceutically acceptable salt thereof and appropriate pharmaceuticaladditives can be pulverized in an ordinary pharmaceutical manner.Examples of a pulverizer include a hammer mill, a ball mill, a jet mill,a colloid mill, and the like. The conditions for pulverization may beappropriately selected and are not particularly limited.

In the step of mixing components subsequent to the pulverization step,both the apparatus and the means are not particularly limited, so longas it is a method in which the components can be uniformly mixed in anordinary pharmaceutical manner.

Granulation Step

In the granulation step, both the apparatus and the means are notparticularly limited, so long as it is a method in which Compound A or apharmaceutically acceptable salt thereof and appropriate pharmaceuticaladditives can be granulated in an ordinary pharmaceutical manner.

Examples of a granulation method and a granulation apparatus, which areused in a wet granulation using a solvent such as water, include a highshear granulation method, a milling (pulverization) granulation method,a fluidized bed granulation method, an extrusion granulation method, atumbling granulation method, and a spray granulation method; andapparatuses and the like, which are used in these methods. A fluidizedbed granulation method and a fluidized bed granulator are preferable,and a drying method is not particularly limited, so long as it can bedried in an ordinary pharmaceutical manner.

During granulation, it is preferable that the water content is low inorder to inhibit a decrease in the proportion of crystals of Compound Aor a pharmaceutically acceptable salt thereof. The water content duringgranulation is, for example, 30% or less, 5% or less in an embodiment,3% or less in an embodiment, 2% or less in an embodiment, and 1% or lessin an embodiment. The granulation method is not particularly limited, solong as the water content can be controlled within the range. Examplesof such a granulation method include a milling (pulverization)granulation method, a fluidized bed granulation method, a tumblinggranulation method, and a spray granulation method; and a fluidized bedgranulation method in an embodiment.

The water content can be measured, for example, by a loss on dryingmethod, or the like. As an apparatus, for example, a halogen moistureanalyzer (METTLER TOLEDO) may be used.

A high shear granulation method can be selected, when conditions capableof reducing the water content in granules during granulation are used.

As a method not using water during granulation, a wet granulation methodusing a non-aqueous solvent, or a dry granulation method, can also beused.

Drying Step

In the drying step, both the apparatus and the means are notparticularly limited, so long as it is a method in which the granulatedproduct can be dried in an ordinary pharmaceutical manner. Examples ofthe apparatus include a forced-air dryer, a dryer under reducedpressure, a vacuum dryer, a fluidized bed granulation dryer, and thelike.

After drying, the dried product may be sieved and sized using a sieve, acomil, or the like, if desired.

Molding Step

In the molding step, both the apparatus and the means are notparticularly limited, so long as it is a method of molding thepharmaceutical composition for oral administration of the presentinvention. Examples of the method include a method in which, without thegranulation and drying step, Compound A or a pharmaceutically acceptablesalt thereof and appropriate pharmaceutical additives are mixed, anddirectly compression-molded to prepare the pharmaceutical compositionfor oral administration; a method in which Compound A or apharmaceutically acceptable salt thereof and appropriate pharmaceuticaladditives are granulated and dried, and compression-molded to preparethe pharmaceutical composition for oral administration; a method inwhich Compound A or a pharmaceutically acceptable salt thereof andappropriate pharmaceutical additives are granulated, and further mixedwith a lubricant, and the mixture is compression-molded to prepare thepharmaceutical composition for oral administration; and the like.

Examples of a tableting machine include a rotary tableting machine, anoil press, and the like.

The conditions for tableting, such as tableting pressure, are notparticularly limited, so long as it is tableting pressure capable ofcompression-molding.

The hardness of the tableted product is not particularly limited, solong as it is not damaged during the manufacturing process, thedistribution process, and the like. The hardness may be, for example, 40to 200 N.

Film Coating Step

After tableting, the surface of the pharmaceutical composition for oraladministration may be film coated.

The method of film coating is not particularly limited, so long as itmay be coated in an ordinary pharmaceutical manner. Examples of thecoating include pan coating, dip coating, and the like.

A film coating agent may be appropriately added alone, or as acombination of two or more, in appropriate amounts.

The coating rate is not particularly limited, so long as a film can beformed. The coating rate is, for example, with respect to the totalweight of the pharmaceutical composition for oral administration, 1% byweight to 10% by weight, or the like.

During film coating or after film coating, the coated product may bedried. The drying method is not particularly limited, so long as it maybe dried in an ordinary pharmaceutical manner. The conditions for dryingare not particularly limited, so long as they are appropriately selectedin view of, for example, the stability of the pharmaceutical compositionfor oral administration.

Crystallization Step

When the proportion of crystals of Compound A or a pharmaceuticallyacceptable salt thereof is reduced, a step of promoting crystallizationmay be adopted. Examples of the step include a microwave irradiationtreatment, an ultrasonic irradiation treatment, a low frequencyirradiation treatment, a thermal electron irradiation treatment, and thelike.

As the microwave irradiation treatment, for example, a wavelength of 10MHz to 25 GHz may be irradiated. Although the treatment time depends onthe degree of an initial crystal proportion, or pharmaceutical additivecomponents, it is performed, for example, for 10 seconds to 60 minutes.The irradiation may be continuous or intermittent, and at any time.

As the ultrasonic irradiation treatment, for example, sound waves with afrequency of 10 kHz to 600 kHz may be irradiated. Although the treatmenttime depends on the degree of a crystal proportion, or pharmaceuticaladditive components, it is performed, for example, for 10 seconds to 24hours. The irradiation may be continuous or intermittent, and at anytime.

The present invention includes a method of stabilizing Compound A or apharmaceutically acceptable salt thereof by the proportion of crystalsof Compound A or a pharmaceutically acceptable salt thereof, and/or by apharmaceutical additive capable of controlling a water content in aformulation.

The present invention includes a use of a pharmaceutical additivecapable of controlling a water content in a formulation, in themanufacture of a stable pharmaceutical composition for oraladministration comprising Compound A or a pharmaceutically acceptablesalt thereof.

With respect to “crystals of Compound A or a pharmaceutically acceptablesalt thereof”, “a pharmaceutical additive capable of controlling a watercontent in a formulation” and “Compound A or a pharmaceuticallyacceptable salt thereof”, which are used in the stabilizing method ofthe present invention, and the use of a pharmaceutical additive capableof controlling a water content in a formulation of the presentinvention, the explanations therefor described in the pharmaceuticalcomposition for oral administration of the present invention can bedirectly applied.

With respect to the content of each component, their blending method,and the like in the stabilizing method of the present invention, and theuse of a pharmaceutical additive capable of controlling a water contentin a formulation of the present invention, the explanations therefordescribed in the pharmaceutical composition for oral administration ofthe present invention and the method of producing the same can bedirectly applied.

EXAMPLES

The present invention will now be further illustrated by, but is by nomeans limited to, the following Comparative Examples, Examples, andExperimental Examples.

Comparative Example 1 and Examples 1 to 3

The formulations of Comparative Example 1 and Examples 1 to 3 are shownin Tables 1 and 2. Compound A hemifumarate, which was used below, hadbeen prepared in accordance with a method described in WO 2010/128659,or in a similar fashion to that

TABLE 1 Comparative Example 1 Example 1 Compound A hemifumarate 11.0544.2 Lactose hydrate 53.75 215.0 Microcrystalline cellulose 4.5 18.0Low-substituted hydroxypropyl cellulose 9.0 36.0 Hydroxypropyl cellulose1.8 7.2 Microcrystalline cellulose 4.5 18.0 Low-substituted hydroxypropycellulose 4.5 18.0 Magnesium stearate 0.9 3.6 Subtotal 90.0 360.0Film-coating agent (Opadry 03F42203) 2.7 10.8 Total 92.7 370.8 Unit: mg

TABLE 2 Example 2 Example 3 Compound A hemifumarate 44.2 44.2 D-mannitol82.5 86.12 Hydroxypropyl cellulose 4.2 4.32 Low-substitutedhydroxypropyl cellulose 7.0 7.2 Magnesium stearate 2.1 2.16 Subtotal140.0 144.0 Film-coating agent (Opadry 03F42203) 4.2 4.3 Total 144.2148.3 Unit: mg

Pharmatose 200M (product name, manufactured by FrieslandCampina DMV BV)was used as lactose hydrate, HPC-L (product name, manufactured by NipponSoda Co., Ltd.) was used as hydroxypropyl cellulose, Parteck LUB MST(product name, manufactured by Merck KGaA) was used as magnesiumstearate, and PEARLITOL 50C (product name, manufactured by ROQUETTE) wasused as D-mannitol.

Comparative Example 1

In accordance with the formulation described in Table 1, 110.5 g ofCompound A hemifumarate, 537.5 g of lactose hydrate, 45 g ofmicrocrystalline cellulose (product name: Ceolus PH-101, manufactured byAsahi Kasei Chemicals Corporation), 90 g of low-substitutedhydroxypropyl cellulose (product name: L-HPC LH-21, manufactured byShin-Etsu Chemical Co., Ltd.), and 18 g of hydroxypropyl cellulose weremixed using a high shear granulator (product name: VG-05, manufacturedby Powrex Corporation), and 300 g of purified water was further addedthereto, and the mixture was granulated. The water content of thegranulated product during granulation was 27%. Two additional lots ofgranulation were performed, and the granulated product was obtained bydrying for 15 hours using a vacuum dryer (product name: DB-30,manufactured by ULVAC, Inc.). After 2403 g of the obtained granulatedproduct was sieved, 135 g of microcrystalline cellulose (product name:Ceolus PH-102, manufactured by Asahi Kasei Chemicals Corporation), 135 gof low-substituted hydroxypropyl cellulose (product name: L-HPC LH-11,manufactured by Shin-Etsu Chemical Co., Ltd.), and 27 g of magnesiumstearate were added thereto, and mixed using a mixer (product name:Container Mixer LM20, manufactured by Kotobuki Industries Co., Ltd.) toobtain a mixed product (granules for tablet compression). The obtainedmixed product was formed into tablets using a rotary tableting machine(product name: HT-X20, manufactured by HATA TEKKOSHO Co., Ltd.) toobtain tablets (uncoated tablets). The obtained uncoated tablets (1350g) were film coated using a film coating machine (product name: HCT-30,manufactured by Freund Corporation) with a liquid, prepared bydissolving/dispersing OPADRY 03F42203 (product name, manufactured byColorcon) in purified water, so that the concentration of OPADRY03F42203 was 10% by weight in total (concentration of solid components).An additional lot of film coating was performed, to obtain tablets (filmcoated tablets) of Comparative Example 1.

Example 1

In accordance with the formulation described in Table 1, 442 g ofCompound A hemifumarate, 2150 g of lactose hydrate, 180 g ofmicrocrystalline cellulose (product name: Ceolus PH-101, manufactured byAsahi Kasei Chemicals Corporation), 360 g of low-substitutedhydroxypropyl cellulose (product name: L-HPC LH-21, manufactured byShin-Etsu Chemical Co., Ltd.), and 72 g of hydroxypropyl cellulose weremixed using a high shear granulator (product name: VG-25, manufacturedby Powrex Corporation), and the mixture was granulated by adding 1170 gof purified water. The water content of the granulated product duringgranulation was 27%. Nine additional lots of granulation were performed,and the granulated product was obtained by drying for 1 hour using afluidized bed granulation dryer (product name: GPCG-PRO-5, manufacturedby Powrex Corporation). After 32040 g of the obtained granulated productwas sieved, 1800 g of microcrystalline cellulose (product name: CeolusPH-102, manufactured by Asahi Kasei Chemicals Corporation), 1800 g oflow-substituted hydroxypropyl cellulose (product name: L-HPC LH-11,manufactured by Shin-Etsu Chemical Co., Ltd.), and 360 g of magnesiumstearate were added thereto, and mixed using a mixer (product name:Container Mixer PM200, manufactured by Kotobuki Industries Co., Ltd.) toobtain a mixed product (granules for tablet compression). The obtainedmixed product was formed into tablets using a rotary tableting machine(product name: HT-CVX-TYPEIII20, manufactured by HATA TEKKOSHO Co.,Ltd.) to obtain tablets (uncoated tablets). The obtained uncoatedtablets (36000 g) were film coated using a film coating machine (productname: PRC-20/60, manufactured by Powrex Corporation) with a liquid,prepared by dissolving/dispersing OPADRY 03F42203 (product name,manufactured by Colorcon) in purified water, so that the concentrationof OPADRY 03F42203 was 10% by weight in total (concentration of solidcomponents), to obtain tablets (film coated tablets) of Example 1.

Example 2

In accordance with the formulation described in Table 2, 6630 g ofCompound A hemifumarate and 12375 g of D-mannitol were mixed using afluidized bed granulation dryer (product name: GPCG-PRO-15, manufacturedby Powrex Corporation). After mixing, the mixture was granulated byspraying 9000 g of a hydroxypropyl cellulose aqueous solution (solidcontent: 7% by weight) as a binder, and dried to obtain a granulatedproduct. The water content of the granulated product during granulationwas 0.43% at the maximum. After 19635 g of the obtained granulatedproduct was sieved, 1050 g of low-substituted hydroxypropyl cellulose(product name: L-HPC LH-21, manufactured by Shin-Etsu Chemical Co.,Ltd.) and 315 g of magnesium stearate were added thereto, and mixedusing a mixer (product name: Container Mixer PM200, manufactured byKotobuki Industries Co., Ltd.) to obtain a mixed product (granules fortablet compression). The obtained mixed product was formed into tabletsusing a rotary tableting machine (product name: HT-CVX-TYPEIII20,manufactured by HATA TEKKOSHO Co., Ltd.) to obtain tablets (uncoatedtablets). The obtained uncoated tablets (21000 g) were film coated usinga film coating machine (product name: PRC-20/60, manufactured by PowrexCorporation) with a liquid, prepared by dissolving/dispersing OPADRY03F42203 (product name, manufactured by Colorcon) in purified water, sothat the concentration of OPADRY 03F42203 was 10% by weight in total(concentration of solid components), to obtain tablets (film coatedtablets) of Example 2.

Example 3

Tablets (film coated tablets) of Example 3 were prepared in a similarmanner to that of Example 2, in accordance with the formulationdescribed in Table 2.

Experimental Example 1 Calculation of Proportion of Crystals

With respect to the tablets (film coated tablets) prepared inComparative Example 1, Example 1, Example 2, and Example 3, theproportion of crystals of Compound A hemifumarate after production wascalculated by near-infrared spectroscopy.

More particularly, the spectrum was measured by a Fourier transformnear-infrared spectrometer (product name: MPA, Bruker Optics K.K.)(measurement range; 12500 cm⁻¹ to 5800 cm⁻¹, resolution; 8 cm⁻¹, numberof scans; 32), and the obtained spectrum was secondary-differentiated(Savitzky-Golay convolution method), and analyzed using a near-infraredspectrum analysis software (product name: OPUS, Bruker Optics K.K.). Thetablets were powdered using a mortar and pestle, and the spectra weremeasured. Before the spectrum measurement of the tablets, spectra ofpreparations, in which crystals of Compound A hemifumarate were mixed invarious proportions, were regression-analyzed by a partial least squaremethod to create a calibration curve, and each spectrum obtained fromthe tablets was interpolated into the calibration curve to calculate theproportion of crystals of Compound A hemifumarate. The results are shownin Table 4.

Experimental Example 2 Measurement of Related Substances

The tablets (film coated tablets) prepared in Comparative Example 1,Example 1, Example 2, and Example 3 were put into bottles, and allowedto stand under opened conditions of 40° C. and 75% RH for 1 month and 3months. Related substances after storage were measured by an HPLCmethod. The measurement of related substances was carried out under thefollowing conditions:

As an HPLC column, Kinetex XB-C18, particle size: 2.6 μm, 4.6 mm (innerdiameter)×75 mm (manufactured by Phenomenex Inc.), or its equivalent,was used, and maintained at 40° C.

As mobile phase A, a perchlorate solution (pH 2.2) was used, and asmobile phase B, acetonitrile was used.

As sample solutions, samples were diluted with a perchlorate solution(pH 2.2)/acetonitrile mixture (=4/1) was used, so that the concentrationof compound A was 0.8 mg/mL.

As a standard solution, a standard was diluted with a perchloratesolution (pH 2.2)/acetonitrile mixture (=4/1) was used, so that theconcentration of compound A was 0.008 mg/mL.

The measurement of related substances was carried out using anultraviolet absorption spectrophotometer (wavelength: 220 nm), inaccordance with the gradient program shown in Table 3 below, and thepercentage of each related substance was calculated based on the ratioof the peak area of each related substance to the peak area of thestandard solution.

The measurement results of a related substance having a relativeretention time of about 1.06 with respect to the peak of Compound A areshown in Table 4.

TABLE 3 Time (min.) Mobile phase A (%) Mobile phase B (%) 0→2 96 4 2→596→85  4→15  5→20 85→68 15→32 20→25 68→30 32→70 25→26 30 70   26→26.130→96 70→4  26.1→30   96 4

TABLE 4 Related substance (%) Opened conditions of Proportion 40° C. and75% RH of At the crystals beginning (%) of test 1 month 3 monthsComparative 26 0.05 0.21 N.T. Example 1 Example 1 64 <LOQ 0.11 0.26Example 2 98 <LOQ <LOQ N.T. Example 3 85 <LOQ <LOQ <LOQ LOQ: Limit ofQuantitation, N.T.: Not Tested

Comparative Example 1 was prepared by a high shear granulation method,as similar to Example 1, but they were different from each other in theproportion of crystals. It is inferred that this is due to thedifference in drying time caused by different drying methods.

In the tablet of Example 1, in which the proportion of crystals ofCompound A hemifumarate was 64%, the percentage of the related substancewas 0.11% after storage under opened conditions of 40° C. and 75% RH for1 month, and the percentage of the related substance was 0.26% afterstorage for 3 months. In the tablets of Examples 2 and 3, the percentageof the related substance after storage for 1 month was less than thelimit of quantitation (LOQ). The tablets of these Examples contained asmall amount of a related substance, in comparison with the tablet ofthe Comparative Example, and were stable. For reference, the LOQ is0.05%.

As described above, it was confirmed that when the proportion ofcrystals of Compound A hemifumarate increased, the generation of relatedsubstances could be inhibited.

Examples 4 to 15

After water was added to the crystals of Compound A hemifumarate, it wasdried to obtain Compound A hemifumarate, of which the proportion ofcrystals was 62%. Various pharmaceutical additives shown in Table 5 werephysically mixed with the obtained Compound A hemifumarate at a weightratio of 1:1, and the obtained pharmaceutical compositions were put intobottles and allowed to stand under opened conditions of 40° C. and 75%RH for 1 month and 3 months.

Experimental Example 3 Measurement of Related Substances

Related substances contained in the pharmaceutical compositions of theExamples were measured in a similar manner to that of ExperimentalExample 2. The measurement results of a related substance having arelative retention time of about 1.06 with respect to the peak ofCompound A are shown in Table 5.

Experimental Example 4 Measurement of Loss on Drying of PharmaceuticalAdditives

The measurement of loss on drying of various pharmaceutical additivesshown in Table 5 was carried out in a similar manner to the test forabove loss on drying. The pharmaceutical additives used were lactosehydrate (product name: Pharmatose 200M, manufactured by FrieslandCampinaDMV BV), hydroxypropyl cellulose (product name: HPC-L, manufactured byNippon Soda Co., Ltd.), magnesium stearate (product name: Parteck LUBMST, manufactured by Merck KGaA), D-mannitol (product name: PEARLITOL50C, manufactured by ROQUETTE), microcrystalline cellulose (productname: Ceolus PH-101, manufactured by Asahi Kasei Chemicals Corporation),anhydrous dibasic calcium phosphate (product name: GS, manufactured byKyowa Chemical Industry Co., Ltd.), hypromellose (product name: TC-5E,Shin-Etsu Chemical Co., Ltd.), corn starch (product name: corn starch,manufactured by Nihon ShokuhinKako Co., Ltd.), low-substitutedhydroxypropyl cellulose (product name: L-HPC LH-21, low-substitutedhydroxypropyl cellulose), croscarmellose sodium (product name: KICCOLATEND-2HS, manufactured by Nichirin Chemical Industries, Ltd.), calciumstearate (product name: Parteck LUB CST, manufactured by Merck KGaA),and talc (product name: Hi-filler, manufactured by Matsumura Sangyo Co.,Ltd.).

TABLE 5 40° C. · 40° C. · 75% RH 75% RH 1 month 3 months Amount ofAmount of Loss on drying related related of substance substance Numberpharmaceutical after after of Pharmaceutical additive storage storageExample additive (%) (%) (%) Reference (Not added) — <LOQ 0.06 valueExample anhydrous 0.20 <LOQ 0.06 4 dibasic calcium phosphate ExampleLactose hydrate 0.26 <LOQ <LOQ 5 Example D-mannitol 0.32 <LOQ <LOQ 6Example Talc 0.46 <LOQ 0.06 7 Example Calcium stearate 0.53 <LOQ 0.06 8Example Magnesium 1.5 <LOQ 0.09 9 stearate Example Microcrystalline 7.80.06 0.10 10 cellulose Example Hydroxypropyl 9.3 0.05 0.11 11 celluloseExample Hypromellose 9.5 <LOQ 0.09 12 Example Corn starch 13.2 0.06 0.1113 Example Low-substituted 13.4 0.05 0.11 14 Hydroxypropyl celluloseExample Croscarmellose 18.6 0.05 0.10 15 sodium LOQ: Limit ofQuantitation

It was confirmed that the pharmaceutical compositions of Examples 4 to15 were stable after 1 month and 3 months under opened conditions of 40°C. and 75% RH, and that when the proportion of crystals of Compound Ahemifumarate increased, the generation of related substances could beinhibited. It was suggested that, in particular, lactose hydrate(Example 5) and D-mannitol (Example 6) were suitable from the viewpointof inhibition of the generation of related substances.

Experimental Example 5 Measurement of Loss on Drying of Tablets ofExamples 2 and 3

The loss on drying of the tablets of Examples 2 and 3 after storageunder opened conditions of 40° C. and 75% RH for 1 week was measured ina similar manner to that of Experimental Example 4. The results areshown in Table 6. The loss on drying in the tablets, which containedD-mannitol in the formulations, was low.

TABLE 6 Loss on drying (%) Example 2 1.3 Example 3 1.4

From the above results, a stable formulation comprising Compound A or apharmaceutically acceptable salt thereof can be provided by controllingthe proportion of crystals of Compound A or a pharmaceuticallyacceptable salt thereof, and/or by using a pharmaceutical additivecapable of controlling a water content in a formulation.

INDUSTRIAL APPLICABILITY

According to the present invention, a stable pharmaceutical compositionfor oral administration comprising Compound A or a pharmaceuticallyacceptable salt thereof, wherein the generation of related substancesduring storage, is inhibited.

Although the present invention has been described with reference tospecific embodiments, various changes and modifications obvious to thoseskilled in the art are possible without departing from the scope of theappended claims.

1. A pharmaceutical composition for oral administration comprising:6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamideor a pharmaceutically acceptable salt thereof and a pharmaceuticaladditive, wherein the pharmaceutical additive exhibits a loss on dryingof 20% or less after storage under opened conditions of 40° C. and 75%relative humidity for 1 week, wherein the pharmaceutical compositionexhibits an increase of no more than 0.11% of an oxidative decompositionproduct having a relative retention time of 1.06 with respect to aretention time of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,as measured by a high-performance liquid chromatography method, afterstorage under opened conditions of 40° C. and 75% relative humidity for1 month, and wherein the high-performance liquid chromatography methodis performed under following conditions: a Kinetex XB-C18 column,particle size: 2.6 μm, 4.6 mm (an inner diameter)=75 mm,; a columntemperature maintained at 40° C.; a mobile phase A of a perchloratesolution (pH 2.2); a mobile phase B of an acetonitrile solution; asample solution having a sample concentration of 0.8 mg/ml of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidein a 4:1 mixture of the perchlorate solution (pH 2.2) and theacetonitrile solution; a standard solution having a standard solutionconcentration of 0.008 mg/ml of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidein a 4:1 mixture of the perchlorate solution (pH 2.2) and theacetonitrile solution; an ultraviolet absorption spectrophotometerdetector with a wavelength at 220 nm; and a gradient of the mobile phaseA and mobile phase B is as follows: (a) from 0 minutes to 2 minutessince sample injection, 96% mobile phase A and 4% mobile phase B; (b)from 2 minutes to 5 minutes since sample injection, 96% incrementingdown to 85% mobile phase A and 4% incrementing up to 15% mobile phase B;(c) from 5 minutes to 20 minutes since sample injection, 85%incrementing down to 68% mobile phase A and 15% incrementing up to 32%mobile phase B; (d) from 20 minutes to 25 minutes since sampleinjection, 68% incrementing down to 30% mobile phase A and 32%incrementing up to 70% mobile phase B; (e) from 25 minutes to 26 minutessince sample injection, 30% mobile phase A and 70% mobile phase B; (f)from 26 minutes to 26.1 minutes since sample injection, 30% incrementingup to 96% mobile phase A and 70% incrementing down to 4% mobile phase B;and (g) from 26.1 minutes to 30 minutes since sample injection, 96%mobile phase A and 4% mobile phase B.
 2. The pharmaceutical compositionaccording to claim 1, wherein the loss on drying of the pharmaceuticaladditive is 1.0% or less.
 3. The pharmaceutical composition according toclaim 1, comprising6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidehemifumarate.
 4. The pharmaceutical composition according to claim 1,wherein a content of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamideor the pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition is 10% by weight to 40% by weight with respect to 100% byweight of the pharmaceutical composition.
 5. The pharmaceuticalcomposition according to claim 1, wherein a pharmaceutical additivecontent in the pharmaceutical composition is 50% by weight to 70% byweight with respect to 100% by weight of the pharmaceutical composition.6. The pharmaceutical composition according to claim 1, wherein apharmaceutical additive content in the pharmaceutical composition is 50%by weight to 60% by weight with respect to 100% by weight of thepharmaceutical composition.
 7. The pharmaceutical composition accordingto claim 1, wherein a pharmaceutical additive weight content in thepharmaceutical composition is 1.5 times to 4.5 times that of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamideor the pharmaceutically acceptable salt thereof.
 8. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical additive isselected from the group consisting of lactose, D-mannitol, anhydrousdibasic calcium phosphate, talc, calcium stearate, magnesium stearate,microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, cornstarch, low-substituted hydroxypropyl cellulose, and croscarmellosesodium.
 9. The pharmaceutical composition according to claim 8, whereinthe pharmaceutical additive is lactose or D-mannitol.
 10. Thepharmaceutical composition according to claim 3, wherein a proportion ofcrystals of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidehemifumarate is 98% or less with respect to a total amount of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidehemifumarate in the pharmaceutical composition.
 11. The pharmaceuticalcomposition according to claim 10, wherein the loss on drying of thepharmaceutical additive is 1.0% or less.
 12. The pharmaceuticalcomposition according to claim 10, comprising 40 mg to 50 mg of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidehemifumarate.
 13. The pharmaceutical composition according to claim 10,wherein a pharmaceutical additive content in the pharmaceuticalcomposition is 50% by weight 70% by weight with respect to 100% byweight of the pharmaceutical composition.
 14. The pharmaceuticalcomposition according to claim 10, wherein a pharmaceutical additivecontent in the pharmaceutical composition is 50% by weight to 60% byweight with respect to 100% by weight of the pharmaceutical composition.15. The pharmaceutical composition according to claim 10, wherein apharmaceutical additive weight content in the pharmaceutical compositionis 1.5 times to 4.5 times that of6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidehemifumarate.
 16. The pharmaceutical composition according to claim 10,wherein the pharmaceutical additive is selected from the groupconsisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate,talc, calcium stearate, magnesium stearate, microcrystalline cellulose,hydroxypropyl cellulose, hypromellose, corn starch, low-substitutedhydroxypropyl cellulose, and croscarmellose sodium.
 17. Thepharmaceutical composition according to claim 10, wherein thepharmaceutical additive is lactose or D-mannitol.
 18. The pharmaceuticalcomposition according to claim 1, which is a tablet.
 19. Thepharmaceutical composition according to claim 3, which is a tablet. 20.The pharmaceutical composition according to claim 12, which is a tablet.